CN104072518A - Preparation method of cefcapene diisopropylamine salt - Google Patents
Preparation method of cefcapene diisopropylamine salt Download PDFInfo
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- CN104072518A CN104072518A CN201410270816.6A CN201410270816A CN104072518A CN 104072518 A CN104072518 A CN 104072518A CN 201410270816 A CN201410270816 A CN 201410270816A CN 104072518 A CN104072518 A CN 104072518A
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- amine salt
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- triethylamine
- diisopropyl amine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Abstract
The invention relates to a preparation method of cefcapene diisopropylamine salt. The preparation method comprises the following steps: (1) obtaining acylate 3 by using cefcapene side chain acid 2 in the presence of an acylation reagent namely SOCl2 and an acid-binding agent namely triethylamine; (2) obtaining a condensation product 5 by using acylate 3 and a 7-HACA raw material 4 in the presence of triethylamine and a catalyst namely 4-dimethylaminopyridine; (3) enabling the condensation product 5 to react with chlorosulfonic acid isocyanate to obtain a 3-bit aminoacyl ester compound 6; (4) performing salt formation on the compound 6 and diisopropylamine to obtain cefcapene diisopropylamine salt 1. According to the preparation method disclosed by the invention, thionyl chloride is used as the acylation reagent, and triethylamine is used as the acid-binding agent so as to reduce the cost; 4-dimethylaminopyridine with the catalyst amount is added in the step (2) to ensure that the reaction is performed more completely and the reaction time is shortened; the preparation method is simple and convenient in whole route operation, and is convenient for large-scale production.
Description
Technical field
The preparation method who the present invention relates to a kind of S-1108 key intermediate S 1006 diisopropyl amine salt, belongs to cephalosporin analog antibiotic technical field of pharmaceuticals.
Background technology
S-1108, chemical name: 7-[(Z)-2-(2-aminothiazole-4-yl)-2-amylene amide group]-3-carboxamide oxygen methyl-3-cephem-4-carboxylic acid pivalyl oxygen methyl esters, CAS registration number is 105889-45-0.S-1108 is the Ceftobiprole/Ceftbiprole Medocaril by the exploitation of Japanese Yan Yeyi company, in the trade(brand)name Initial Public Offering with Flomox in 1997, for the third generation can oral cephalosporin analog antibiotic.Mainly be applicable to respiratory tract infection due to sensitive organism as pneumonia, bronchitis, pharyngolaryngitis, tonsillitis etc.; Otitis media; Sinusitis paranasal sinusitis; Urinary tract infections is as gonorrhoea, pyelonephritis, urocystitis; Skin and skin histology infection etc.; Biliary tract infection etc.
S 1006 (Cefcapene) is an intermediate preparing S-1108 hydrochloride monohydrate, at WO2008155615, in the document such as CN101717344 and CN100361996, this intermediate or with free acid or taking its inorganic salt (often as sodium salt, sylvite) form exist, but be that follow-up esterification is need to add mineral alkali to prepare inorganic salt time forming the process of inorganic salt or its free acid, cephem carboxylic mother nucleus structure is subject to destruction under inorganic strong alkali environment, cause yield low, poor product quality, therefore in S-1108 preparation process, should avoid using inorganic strong alkali as far as possible.
S 1006 Diisopropylamine salt chemical name is: (6R, 7R)-7-[[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-2-amylene acyl] amino]-3-carbamyl oxygen methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic diisopropylamine.CN102775425 provides a kind of preparation method that treats different things alike of S 1006 diisopropyl amine salt, but in this patent documentation, does not report the purity of this intermediate, and due to one pot reaction, causes a large amount of by products, is difficult to meet the requirement of medicine intermediate.Document (J.-A. Jiang, et.al,
synthesis 2012,
44, 207 – 214) also report and the preparation method of this compound used a large amount of Diisopropylamines and methylsulfonyl chloride, although that reaction is carried out is comparatively complete, cost is higher, is unfavorable for suitability for industrialized production.
Summary of the invention
The invention provides a kind of preparation method of S 1006 diisopropyl amine salt, the preparation method of S 1006 diisopropyl amine salt provided by the invention, adopts following technical scheme:
(1) S 1006 side-chain acid 2 is at acylating reagent SOCl
2and under the existence of acid binding agent triethylamine, obtain acylate 3;
(2) acylate 3, with 7-HACA raw material 4 under triethylamine and the existence of catalyzer DMAP, obtains condensation product 5;
(3) condensation product 5 reacts with chlorsulfonic acid isocyanide ester, obtains 3 amino acyl esters compounds 6;
(4) compound 6 obtains S 1006 diisopropyl amine salt 1 with diisopropylamine salify, and reaction scheme is as follows:
。
Wherein, preparation method's step described above (1) solvent for use is methylene dichloride, and temperature of reaction is-15-10 DEG C, and the reaction times is 1-3 hour, and raw materials used 2 with the mol ratio of thionyl chloride and triethylamine are: 1:1.0 ~ 1.2:1.0 ~ 1.2.
Preparation method's step described above (2) solvent for use is methylene dichloride; temperature of reaction is-15-10 DEG C; reaction times is 1-3 hour, acylate 3 used, 7-HACA raw material 4,, the mol ratio of triethylamine and DMAP is: 1:1.0 ~ 1.2:1.0 ~ 1.2:0.05 ~ 0.1.
In preparation method's step described above (3), solvent is one or more in methylene dichloride, ethyl acetate, acetonitrile, preferably methylene dichloride; Temperature of reaction is-20-15 DEG C, and the reaction times is 1-8 hour, and raw materials used 5 with the mol ratio of chlorsulfonic acid isocyanide ester are: 1:1.0 ~ 1.2.
Carry out salt-forming reaction to dripping diisopropylamine in the solution of preparation method's step described above (3), make organic salt solid, suction filtration, obtains white powder target product.
Beneficial effect of the present invention:
(1) step (1) adopts thionyl chloride to do acylating reagent, does acid binding agent with triethylamine, has reduced cost;
(2) in step (2), add the DMAP of catalytic amount, what make that reaction carries out is more complete, has shortened the time of reaction;
(3) after, two-step reaction is treated different things alike, easy and simple to handle, is convenient to large-scale production.
embodiment:
Below by embodiment, the present invention will be further described, but protection scope of the present invention is not limited to this.
embodiment 1
Get 29.8g (0.10mol) raw material 1 in reaction flask, add methylene dichloride 250ml and 10.1g(0.10mol) triethylamine dissolve after be cooled to-10 DEG C, slowly drip 13.1g (0.11mol) thionyl chloride reagent, at this temperature, stir after 1 hour.To the hydrochloride, 20ml methyl alcohol and the 22.8ml (20.2g that slowly drip 26.7g (0.10mol) 7-HACA in reacted solution, 0.2mol) triethylamine and 1.22g(0.01mol) solution that forms of DMAP, keep reaction solution-10 DEG C of lasting stirring reactions 2 hours, filter, collect filtrate, the sodium hydroxide solution with 5% regulates filtrate pH=8.Divide water-yielding stratum, decolouring, then drips the hydrochloric acid of 1mol/L to pH=2, filter, and washing, vacuum-drying obtains 47.1g midbody product 5, yield 92.1%, HPLC normalization method content 95.2%.
By the 25.5g(0.05mol obtaining) midbody product 5 is dissolved in 200ml methylene dichloride, cools to-20 DEG C, slowly drips Sulfuryl chloride isocyanate CSI 7.76g (0.055mol), insulated and stirred reaction solution 1 hour at this temperature.Reaction solution is warming up to room temperature naturally, adds 100ml water to stir, separatory is removed water layer, and organic phase is adjusted pH to 2 with the hydrochloric acid soln of 1mol/L, discards water layer, washing organic phase.Organic phase solution is cooled to 0 DEG C, add 7.1ml (5.1g, Diisopropylamine 0.05mol), stirring 30min gradually adularescent solid separates out, and is naturally warming up to 25 DEG C of suction filtrations, and filter cake is washed by 120ml ethyl acetate, vacuum-drying, obtain 29.6g powdery white solid, yield 90.5%, HPLC normalization method content 97.4%.
embodiment 2
Get 298g (1.0mol) raw material 1 in reaction flask, add methylene dichloride 2500ml and 101g(1.0mol) triethylamine dissolve after be cooled to-10 DEG C, slowly drip 131g (1.1mol) thionyl chloride reagent, at this temperature, stir after 1 hour.To the hydrochloride, 200ml methyl alcohol and the 228ml (202g that slowly drip 267g (1.0mol) 7-HACA in reacted solution, 2.0mol) triethylamine and 12.2g(0.1mol) solution that forms of DMAP, keep reaction solution-10 DEG C of lasting stirring reactions 3 hours, filter, collect filtrate, the sodium hydroxide solution with 5% regulates filtrate pH=8.Divide water-yielding stratum, decolouring, then drips the hydrochloric acid of 1mol/L to pH=2, filter, and washing, vacuum-drying obtains 462g midbody product 5, yield 90.6%, HPLC normalization method content 94.7%.
By the 255g(0.5mol obtaining) midbody product 5 is dissolved in 2000ml methylene dichloride, cools to-20 DEG C, slowly drips Sulfuryl chloride isocyanate CSI 77.6g (0.55mol), insulated and stirred reaction solution 2 hours at this temperature.Reaction solution is risen to room temperature naturally, add 1000ml water to stir, separatory is removed water layer, and organic phase is adjusted pH to 2 with the hydrochloric acid soln of 1mol/L, discards water layer, washing organic phase.Organic phase solution is cooled to 0 DEG C, add 71ml (51g, Diisopropylamine 0.5mol), stir 1 hour gradually adularescent solid separate out, be naturally warming up to 25 DEG C of suction filtrations, filter cake is washed by 1200ml ethyl acetate, vacuum-drying, obtain 287g powdery white solid, yield 87.8%, HPLC normalization method content 97.0%.
Claims (8)
1. a preparation method for S 1006 diisopropyl amine salt, is characterized in that comprising the following steps:
(1) S 1006 side-chain acid 2 is at acylating reagent SOCl
2and under the existence of acid binding agent triethylamine, obtain acylate 3;
(2) acylate 3, with 7-HACA raw material 4 under triethylamine and the existence of catalyzer DMAP, obtains condensation product 5;
(3) condensation product 5 reacts with chlorsulfonic acid isocyanide ester, obtains 3 amino acyl esters compounds 6;
(4) compound 6 obtains S 1006 diisopropyl amine salt 1 with diisopropylamine salify;
。
2. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 1, is characterized in that, step (1) and step (2) can be carried out one pot reaction.
3. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 1, is characterized in that, step (1), step (2), step (3) and step (4) can be carried out one pot reaction.
4. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 1, it is characterized in that, the solvent of step (1) is methylene dichloride, temperature of reaction is-15-10 DEG C, reaction times is 1-3 hour, and raw materials used 2 with the mol ratio of thionyl chloride and triethylamine are: 1:1.0 ~ 1.2:1.0 ~ 1.2.
5. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 1; it is characterized in that; step (2) solvent for use is methylene dichloride; temperature of reaction is-15-10 DEG C; reaction times is 1-3 hour, and the mol ratio of acylate 3 used, 7-HACA raw material 4, triethylamine and DMAP is: 1:1.0 ~ 1.2:1.0 ~ 1.2:0.05 ~ 0.1.
6. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 1, is characterized in that, step (3) solvent for use is
One or more in methylene dichloride, ethyl acetate, acetonitrile.
7. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 6, is characterized in that, step (3) solvent for use is
Methylene dichloride.
8. the preparation method of S 1006 diisopropyl amine salt as claimed in claim 1, is characterized in that, step (3) temperature of reaction is-20-15 DEG C, and the reaction times is 1-8 hour, and raw materials used 5 with the mol ratio of chlorsulfonic acid isocyanide ester are: 1:1.0 ~ 1.2.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106220648A (en) * | 2016-07-30 | 2016-12-14 | 济南康和医药科技有限公司 | The synthesis of a kind of tertbutyloxycarbonyl cefcapene diisopropylamine and purification process |
| CN108033971A (en) * | 2017-12-29 | 2018-05-15 | 湖北凌晟药业有限公司 | A kind of synthetic method of Method of cefcapene pivoxil hydrochloride |
| CN111039959A (en) * | 2019-12-20 | 2020-04-21 | 湖北凌晟药业有限公司 | Method for purifying BCN (BCN-cefcapene pivoxil precursor |
| CN114014877A (en) * | 2021-11-29 | 2022-02-08 | 湖北凌晟药业有限公司 | Method for synthesizing cefcapene acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5639877A (en) * | 1993-07-30 | 1997-06-17 | Biochemie Gesellschaft M.B.H. | Intermediates in the synthesis of cephalosporins |
| JP2002000266A (en) * | 2000-06-23 | 2002-01-08 | Shionogi & Co Ltd | Immobilized enzyme of acetyl hydrolase |
| CN102775425A (en) * | 2011-05-12 | 2012-11-14 | 华东理工大学 | Method for preparing Boc-Cefcapene through one-pot boiling |
| CN103848851A (en) * | 2012-11-29 | 2014-06-11 | 上海交通大学 | Synthetic method of cefcapene pivoxil hydrochloride |
-
2014
- 2014-06-18 CN CN201410270816.6A patent/CN104072518A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5639877A (en) * | 1993-07-30 | 1997-06-17 | Biochemie Gesellschaft M.B.H. | Intermediates in the synthesis of cephalosporins |
| JP2002000266A (en) * | 2000-06-23 | 2002-01-08 | Shionogi & Co Ltd | Immobilized enzyme of acetyl hydrolase |
| CN102775425A (en) * | 2011-05-12 | 2012-11-14 | 华东理工大学 | Method for preparing Boc-Cefcapene through one-pot boiling |
| CN103848851A (en) * | 2012-11-29 | 2014-06-11 | 上海交通大学 | Synthetic method of cefcapene pivoxil hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 唐磊等: "头孢卡品前体酸的合成", 《天津化工》, vol. 27, no. 2, 31 March 2013 (2013-03-31) * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106220648A (en) * | 2016-07-30 | 2016-12-14 | 济南康和医药科技有限公司 | The synthesis of a kind of tertbutyloxycarbonyl cefcapene diisopropylamine and purification process |
| CN106220648B (en) * | 2016-07-30 | 2018-08-31 | 济南康和医药科技有限公司 | A kind of synthesis of tertbutyloxycarbonyl Cefcapene diisopropylamine and purification process |
| CN108033971A (en) * | 2017-12-29 | 2018-05-15 | 湖北凌晟药业有限公司 | A kind of synthetic method of Method of cefcapene pivoxil hydrochloride |
| CN111039959A (en) * | 2019-12-20 | 2020-04-21 | 湖北凌晟药业有限公司 | Method for purifying BCN (BCN-cefcapene pivoxil precursor |
| CN111039959B (en) * | 2019-12-20 | 2021-05-04 | 湖北凌晟药业有限公司 | Method for purifying BCN (BCN-cefcapene pivoxil precursor |
| CN114014877A (en) * | 2021-11-29 | 2022-02-08 | 湖北凌晟药业有限公司 | Method for synthesizing cefcapene acid |
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